Biomedical subjects

Moses Rodriguez

Publications and source records attributed to Moses Rodriguez.

27 records · Page 2Linked to original sources

PubMed2002

Enzymatic properties of rat myelencephalon-specific protease.

Myelencephalon-specific protease (MSP), first identified in the rat and now known to have a human homologue (human kallikrein 6), is preferentially expressed in the central nervous system (CNS), compared with nonneural tissues. MSP has been postulated to have trypsin-like activity, is upregulated in response to glutamate receptor-mediated excitotoxic injury in the CNS, and is downregulated in the brain of Alzheimer's patients. The preferential expression of this enzyme by oligodendrocytes in CNS white matter points to a role in myelin homeostasis. To further characterize the activity and substrate specificity of this newly identified enzyme, we have heterologously expressed MSP in a baculovirus/insect cell line system. We demonstrate that recombinant MSP exhibits a broad specificity for cleavage after arginine but not lysine residues, with kinetic characteristics intermediate between trypsin and pancreatic kallikrein. We show that the pro form of MSP does not self-activate but, rather, requires cleavage after lysine, indicating that mature active MSP is regulated by a distinct protease. MSP may be regulated in part by autolysis, since the active protein is readily inactivated through autolysis at specific internal arginine positions. Additionally, we show that MSP is abundantly expressed in inflammatory cells at sites of demyelination in the Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis (MS). In conjunction with data demonstrating the ability of MSP to degrade myelin-associated as well as several extracellular matrix proteins, these findings delineate MSP as a broad-specificity arginine-specific protease with the potential to play a key role in immune-mediated demyelination.

Animals↗

PubMed2002

Cellular sources and targets of IFN-gamma-mediated protection against viral demyelination and neurological deficits.

IFN-gamma is an anti-viral and immunomodulatory cytokine critical for resistance to multiple pathogens. Using mice with targeted disruption of the gene for IFN-gamma, we previously demonstrated that this cytokine is critical for resistance to viral persistence and demyelination in the Theiler's virus model of multiple sclerosis. During viral infections, IFN-gamma is produced by natural killer (NK) cells, CD4(+) and CD8(+) T cells; however, the proportions of lymphocyte subsets responding to virus infection influences the contributions to IFN-gamma-mediated protection. To determine the lymphocyte subsets that produce IFN-gamma to maintain resistance, we used adoptive transfer strategies to generate mice with lymphocyte-specific deficiencies in IFN-gamma-production. We demonstrate that IFN-gamma production by both CD4(+) and CD8(+) T cell subsets is critical for resistance to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelination and neurological disease, and that CD4(+) T cells make a greater contribution to IFN-gamma-mediated protection. To determine the cellular targets of IFN-gamma-mediated responses, we used adoptive transfer studies and bone marrow chimerism to generate mice in which either hematopoietic or somatic cells lacked the ability to express IFN-gamma receptor. We demonstrate that IFN-gamma receptor must be present on central nervous system glia, but not bone marrow-derived lymphocytes, in order to maintain resistance to TMEV-induced demyelination.

Animals↗

PubMed2002

Growth factor treatment of demyelinating disease: at last, a leap into the light.

Researchers seeking treatments for multiple sclerosis (MS) have long dreamed of using neurotrophic factors to enhance remyelination. Previous attempts to apply trophic support for oligodendrocytes in experimental demyelination uniformly produced complicated outcomes that reflected unexpected effects on immune or inflammatory responses and could be interpreted only with caution. Now, two recent publications have demonstrated convincingly that cytokines of the interleukin (IL)-6 superfamily can ameliorate experimental autoimmune encephalomyelitis and promote oligodendrocyte survival, without demonstrable effect on inflammation or immune responses.

Animals↗

PubMed2002

ICAM-1 is crucial for protection from TMEV-induced neuronal damage but not demyelination.

Previous work has suggested that the factors protecting mice from Theiler's murine encephalomyelitis virus (TMEV)-induced spinal cord demyelination are distinct from those involved in protection of the brain during the acute encephalitic phase. In this study, we examined the requirement for intercellular adhesion molecule-1 (ICAM-1) in both of these processes. During the acute phase of infection (days 7 to 10 after intracerebral infection with TMEV), no differences in brain or spinal cord pathology or virus burdens were observed between ICAM-1-knockout mice and the infected immunocompetent control mice of a similar background. Examination of brain pathology later in infection (that is, day 45 post infection [p.i.]) revealed that ICAM-1-deficient mice experienced increased levels of pathology in gray matter regions of the brain. We observed an increase in striatal damage and meningeal inflammation in the brains of TMEV-infected ICAM-1-knockout mice compared to C57BL/6J mice. Despite the increase in brain pathology, no immunoreactivity to viral antigens was detected, suggesting that the virus had been cleared by this time. Resistance to demyelination was similar in both groups, indicating that the resulting immune response was sufficient for protection of the spinal cord white matter.

Animals↗

PubMed2002

Transgenic expression of Theiler's murine encephalomyelitis virus genes in H-2(b) mice inhibits resistance to virus-induced demyelination.

We investigated the role of the immune system in protecting against virus-induced demyelination by generating lines of transgenic B10 (H-2(b)) congenic mice expressing three independent contiguous coding regions of the Theiler's murine encephalomyelitis virus (TMEV) under the control of a class I major histocompatibility complex (MHC) promoter. TMEV infection of normally resistant B10 mice results in virus clearance and development of inflammatory demyelination in the spinal cord. Transgenic expression of the viral capsid genes resulted in inactivation of virus-specific CD8(+) T lymphocytes (class I MHC immune function) directed against the relevant peptides, but it did not affect production of virus capsid-specific antibodies or lymphocyte proliferation to the virus antigen (class II MHC immune functions). Following intracerebral infection with TMEV, all three lines of mice survived the acute encephalitis but transgenic mice expressing VP1 (or the cluster of virus capsid proteins [VP4, VP2, and VP3] mapping to the left of VP1 in the TMEV genome) developed virus persistence and subsequent demyelination in spinal cord white matter. Transgenic mice expressing noncapsid proteins mapping to the right of VP1 (2A, 2B, 2C, 3A, 3B, 3C, and 3D) cleared the virus and did not develop demyelination. These results are consistent with the hypothesis that virus capsid gene products of TMEV stimulate class I-restricted CD8(+) T-cell immune responses, which are important for virus clearance and for protection against myelin destruction. Presented within the context of self-antigens, inactivation of these cells by ubiquitous expression of relevant virus capsid peptides partially inhibited resistance to virus-induced demyelination.

Animals↗

PubMed2002

Incidence of seizures in patients with multiple sclerosis: a population-based study.

OBJECTIVE: To determine whether multiple sclerosis (MS) is associated with occurrence of seizure activity. PATIENTS AND METHODS: The medical records of all incidence patients with MS in Olmsted County, Minnesota, from 1935 to 1991 were reviewed. The incidence of seizures was calculated by using 3 methods: including only seizures that occurred after definite diagnosis of MS, including all seizures occurring after onset of the first symptoms of MS, and including any seizures regardless of the time of onset relative to MS. These incidences were age-adjusted to the 1970 US population and then compared with the age-adjusted incidence rate of seizures in the general population of Olmsted County. RESULTS: The age-adjusted incidence of seizures among MS patients was not significantly higher than the age-adjusted incidence of seizures in the general population of Olmsted County. The age-adjusted incidence of first unprovoked seizures in Rochester, Minn, was 61 per 100,000 person-years. In patients with the definite diagnosis of MS, the age-adjusted Incidence was calculated at 61 per 100,000 person-years (95% confidence interval [CI], 7-114). In the group with seizures after onset of symptoms, the age-adjusted incidence rate was 80 per 100,000 person-years (95% CI, 24-135). In the group with seizures at any time in their life, the age-adjusted incidence rate was 82 per 100,000 person-years (95% CI, 41-158). CONCLUSION: The present study does not suggest that occurrence of seizures is more common in MS patients than in the general population.

Adult↗

PubMed2002

Multiple sclerosis update.

Multiple sclerosis (MS) is the most common cause of neurological disability in young European and North American adults. It is defined as dysfunction in different parts of the central nervous system at different points in time. The etiology is likely autoimmune, resulting from environmental and genetic factors. This article summarizes the symptoms, progression, diagnosis, and treatment of MS. MRI and CSF studies have been extremely helpful in identifying individual cases, but the diagnosis remains a clinical diagnosis, and one of exclusion. Methylprednisolone remains the preferred treatment for acute relapses, although plasma exchange has been shown to be helpful in cases when methylprednisolone has failed. Preventive immunomodulatory treatments are the focus of many current research efforts. Although these treatments have been shown to reduce the frequency of MS attacks, the reduction is modest, at 30%. The data that these drugs alter the progression of disability is less compelling.

Adjuvants, Immunologic↗

PubMed1998

Absence of neurological deficits following extensive demyelination in a class I-deficient murine model of multiple sclerosis.

Demyelination alone has been considered sufficient for development of neurological deficits following central nervous system (CNS) disease. However, extensive demyelination is not always associated with clinical deficits in patients with multiple sclerosis (MS), the most common primary demyelinating disease in humans. We used the Theiler's murine encephalomyelitis virus model of demyelination to investigate the role of major histocompatibility complex (MHC) class I and class II gene products in the development of functional and neurophysiological deficits following demyelination. We measured spontaneous clinical activity by two independent assays and recorded hind-limb motor-evoked potentials in infected class I-deficient and class II-deficient mice of an identical genetic background as well as in highly susceptible SJL/J mice. The results show that despite a similar distribution and extent of demyelinated lesions in all mice, only class I-deficient mice were functionally normal. We propose that the mechanism by which demyelinated class I-deficient mice maintain neurologic function results from increased sodium channel densities and the relative preservation of axons. These findings are the first to implicate a role for MHC class I in the development of neurological deficits following demyelination.

Animals↗

PubMed1997

Primary demyelination in transgenic mice expressing interferon-gamma.

Ever since the use of interferon-gamma to treat patients with multiple sclerosis resulted in enhanced disease, the role of IFN-gamma in demyelination has been under question. To address this issue directly, transgenic mice were generated that expressed the cDNA of murine IFN-gamma in the central nervous system by using an oligodendrocyte-specific promoter. Expression of the transgene occurred after 8 weeks of age, at which time the murine immune and central nervous systems are both fully developed. Directly associated with transgene expression, primary demyelination occurred and was accompanied by clinical abnormalities consistent with CNS disorders. Additionally, multiple hallmarks of immune-mediated CNS disease were observed including upregulation of MHC molecules, gliosis and lymphocytic infiltration. These results demonstrate a direct role for IFN-gamma as an inducer of CNS demyelination leading to disease and provide new opportunities for dissecting the mechanism of demyelination.

Animals↗